The invention relates to the treatment of lipid storage disease with compounds that inhibit glucosyltransferase activity in the affected cells. It relates particularly to the use of 1,5-dideoxy-1,5-imino-D-glucitol and derivatives thereof.
More than 40 million people worldwide are chronically infected with the hepatitis C virus (HCV), and this represents one of the most serious threats to the public health of developed nations (Hoofnagle et al., 1997, New Engl J Med 336:347-356). Hepatitis C infection is the cause of more than 10,000 deaths annually in the United States (Hepatitis C Treatment, Washington Post, Nov. 11, 1997, at A2), a number that is expected to triple in the next twenty years in the absence of effective intervention. Chronic HCV also increases the risk of liver cancer. There are more than 40 million people worldwide who are chronically infected with HCV, representing one of the most serious threats to the public health of developed nations (Hoofnagle et al., 1997). Persistent infection develops in as many as 85% of HCV patients and in at least 20% of these patients the chronic infection leads to cirrhosis within twenty years of onset of infection. With an estimated 3.9 million North Americans chronically infected, complications from Hepatitis C infection is now the leading reason for liver transplantation in the United States.
HCV is an RNA virus belonging to the Flaviviridae family. Individual isolates consist of closely related, yet heterologous populations of viral genomes. This genetic diversity enables the virus to escape the host""s immune system, leading to a high rate of chronic infection.
Therapeutic interventions which are effective for treatment of HCV infection are limited in number and effectiveness. Standard treatment for HCV infection includes administration of interferon-alpha. However, interferon-alpha is of limited use in about 20% of the HCV-infected population (Hoofnagle et al., 1997) and treatment with this compound results in long-term improvement in only 5% of patients. Furthermore, the complications and limitations of interferon-alpha seriously limit the applicability of the treatment. An experimental treatment comprising administration of interferon-alpha and ribavirin (1-xcex1-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) resulted in long-term improvement in only half of patients suffering a relapse of HCV infection (Hepatitis C Treatment Washington Post, Nov. 11, 1997, at A2). Clearly, the disappointing results with interferon must prompt a search for more effective and less toxic therapeutics. Thus, a critical need remains for a therapeutic intervention that effectively treats HCV infection.
In addition to those people chronically infected with HCV, there are more than 350 million people chronically infected with HBV. More than 150 million of these people are likely to die from liver disease in the absence of intervention. As many as 20 million HBV carriers reside in developed nations, as do most HCV carriers.
A large number of individuals who are infected with HCV are also infected with HBV. The therapy for combined HBV/HCV infection is particularly challenging because the HBV and HCV viruses differ from one another in therapeutically significant ways. HBV is a hepadnavirus, while HCV is a pestivirus. HBV is a DNA-containing virus, the genome of which is replicated in the nucleus of the infected cell using a combination of a DNA-dependent RNA polymerase and an RNA-dependent DNA polymerase (i.e., a reverse transcriptase). HCV is an RNA-containing virus, the genome of which is replicated in the cytoplasm of the infected cell using one or more types of RNA-dependent RNA polymerases. Despite the frequent concurrence of HBV infection and HCV infection, a number of compounds known to be effective for treating HBV infection are not effective against HCV. For example, lamivudine (the nucleoside analog 3TC) is useful for treating HBV infection, but is not useful for treating HCV infection. The difference in the susceptibility of HBV and HCV to antiviral agents no doubt relates to their genetically based replicative differences. There remains a particularly critical need for a therapeutic intervention that effectively treats both HBV and HCV infection.
Animal viruses that acquire their envelope from a membrane associated with the intracellular membrane of an infected animal cell cause significant losses to the livestock industry (Sullivan et al., 1995, Virus Res 38:231-239). Such animal viruses include pestiviruses and flaviviruses such as bovine viral diarrhea virus (BVDV), classical swine fever virus, border disease virus, and hog cholera virus.
The flavivirus group to which HCV belongs is known to include the causative agents of numerous human diseases transmitted by arthropod vectors. Human diseases caused by flaviviruses include various hemorrhagic fevers, hepatitis, and encephalitis. Viruses known to cause these diseases in humans have been identified and include, for example, yellow fever virus, dengue viruses 1-4, Japanese encephalitis virus, Murray Valley encephalitis virus, Rocio virus, West Nile fever virus, St. Louis encephalitis virus, tick-borne encephalitis virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, and Kyasanur forest disease virus. A critical need therefore also exists for treating animals, as well as humans, infected with a flavivirus or a pestivirus.
The invention provides a method of inhibiting morphogenesis of a virus which acquires its envelope from a membrane associated with the intracellular membrane of an infected cell, the method comprising administering to the cell a glucosidase inhibitor in an amount effective to inhibit the activity of a glucosidase enzyme associated with the endoplasmic reticulum of the cell. In one aspect, the virus is selected from the group consisting of a flavivirus and a pestivirus, such as a Hepatitis C virus, a bovine viral diarrhea virus, a classical swine fever virus, a border disease virus, or a hog cholera virus. In another aspect, the membrane is selected from the group consisting of a membrane that surrounds the lumen of the endoplasmic reticulum and a membrane that surrounds a lumen of the Golgi apparatus.
In a preferred embodiment of the invention, the glucosidase inhibitor is 1,5-dideoxy-1,5-imino-D-glucitol or a derivative thereof selected from the group consisting of an N-alkyl, N-acyl, N-aroyl, N-aralkyl, and O-acyl derivatives.
The invention includes a method of inhibiting morphogenesis of a virus that acquires its envelope from an internal cell membrane associated with the endoplasmic reticulum (ER). The method comprises administering a glucosidase inhibitor to the cell in an amount effective to inhibit the activity of a glucosidase enzyme associated with the endoplasmic reticulum of the cell, thereby inhibiting morphogenesis of the virus. Mammalian cells infected with the subject viruses including, but not limited to, human liver cells and bovine monocytes are particularly contemplated as therapeutic targets.
The invention also includes a method of treating an animal infected with a virus that is characterized by acquiring its envelope from a membrane associated with the ER of a virus-infected cell. The method comprises administering a glucosidase inhibitor to the animal in an amount effective to inhibit the activity of a glucosidase enzyme with the endoplasmic reticulum of a virus-infected cell of the animal, thereby reducing, ablating, or diminishing the virus infection in the animal. The animal is preferably a mammal such as a pig or a cow and, particularly, a human being.
The methods of the invention are useful for inhibiting morphogenesis of a virus, or for treating an animal infected with any virus that acquires its envelope from a membrane associated with the ER. Because both flaviviruses and pestiviruses acquire their envelopes from membranes associated with the ER, the methods of the invention are contemplated to be particularly useful for inhibiting morphogenesis of, or for treatment of infection by flaviviruses and pestiviruses. Infections by flaviviruses include, but are not limited to, those caused by yellow fever virus, dengue viruses 1-4, Japanese encephalitis virus, Murray Valley encephalitis virus, Rocio virus, West Nile fever virus, St. Louis encephalitis virus, tick-borne encephalitis virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, and Kyasanur forest disease virus. Infections by pestiviruses include, but are not limited to, those caused by HCV, rubella virus, BVDV, classical swine fever virus, border disease virus, and hog cholera virus.
According to yet another aspect of the invention, there is provided a method for targeting a glucosidase inhibitor or glucosyltransferase inhibitor to the liver cell of an animal by targeting said liver cells with an N-alkyl derivative of a 1,5-dideoxy-1,5-imino-D-glucitol. In a preferred embodiment the derivative is an N-nonyl-1,5-dideoxy-1 ,5-imino-D-glucitol.
According to another aspect of the invention there is provided a method for treating lipid storage disease, where a glucosyl- or galactosyl-linked lipid accumulates in the cells of the affected individual. In one embodiment of this aspect of the invention the method comprises treating a lysosomal storage disease in an animal by administering an effective glucosyltransferase-inhibiting amount of an N-nonyl-1,5-dideoxy-1,5-imino-D-glucitol derivative to the affected cells of said animal, whereby the production of glycolipids in said cells is limited. In a preferred embodiment of this aspect of the invention, the animal is affected with Tay-Sachs, Gaucher, Krabbe, or Fabry disease.
According to yet another aspect of the invention there is provided a prophylactic method for protecting a mammal infected by a virus that acquires a viral component from an internal membrane of an animal cells from developing a cancer that is among the sequelae of infection by said virus, comprising administering to the virus infected cell of the animal an effective anti-viral amount of an animal cell glucosidase-inhibitor. In a preferred embodiment of this aspect of the invention the antiviral glucosidase inhibitor is selected from the group consisting of 1,5-dideoxy-1,5-imino-D-glucitol and derivatives thereof.